Objectives: To isolate a plant-derived compound with efflux inhibitory activity towards the NorA transporter of Staphylococcus aureus.Methods: Bioassay-guided isolation was used, with inhibition of ethidium bromide efflux via NorA as a guide. Characterization of activity was carried out using MIC determination and potentiation studies of a fluoroquinolone antibiotic in combination with the isolated compound. Everted membrane vesicles of Escherichia coli cells enriched with NorA were prepared to study efflux inhibitory activity in an isolated manner.Results: The ethanolic extract of Persea lingue was subjected to bioassay-guided fractionation and led to the isolation of the known compound kaempferol-3-O-a-L-(2,4-bis-E-p-coumaroyl)rhamnoside (compound 1). Evaluation of the dose-response relationship of compound 1 showed that ethidium bromide efflux was inhibited, with an IC 50 value of 2 mM. The positive control, reserpine, was found to have an IC 50 value of 9 mM. Compound 1 also inhibited NorA in enriched everted membrane vesicles of E. coli. Potentiation studies revealed that compound 1 at 1.56 mg/L synergistically increased the antimicrobial activity of ciprofloxacin 8-fold against a NorA overexpresser, and the synergistic activity was exerted at a fourth of the concentration necessary for reserpine. Compound 1 was not found to exert a synergistic effect on ciprofloxacin against a norA deletion mutant. The 2,3-coumaroyl isomer of compound 1 has been shown previously not to cause acute toxicity in mice at 20 mg/kg/day. Conclusions:Our results show that compound 1 acts through inhibition of the NorA efflux pump. Combination of compound 1 with subinhibitory concentrations of ciprofloxacin renders a wild-type more susceptible and a NorA overexpresser S. aureus susceptible.

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Anti-staphylococcal activity of Chilean medicinal plants traditionally used by the Huilliche people for wound healing therapy was evaluated against nine Staphylococcus aureus strains. Three extracts of 26 plant samples (20 species) were evaluated by agar overlay bioautography and MIC determination. Total phenolics and tannins were determined, and the antibacterial contribution of the latter was evaluated. The diffusion assay showed that 17 species were active against susceptible S. AUREUS and that 15 species were active against resistant S. aureus. Removal of tannins from extracts rendered only six species active. MIC-determination showed that 20 extracts had antibacterial activity on all eight strains, and the most potent MIC value was 64 µg/mL. Remarkably, 37 extracts were active against the otherwise multidrug-resistant vanthida strain. Our findings support the wound healing properties of Huilliche medicinal plants and the hypothesis that these plants are promising sources of potential anti-staphylococcal agents towards multidrug-resistant strains.

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